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Asymmetric Total Syntheses of Ecteinascidin 597 and Ecteinascidin 583.

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Natural Products Synthesis
DOI: 10.1002/ange.200603179
Asymmetric Total Syntheses of Ecteinascidin 597
and Ecteinascidin 583**
Jinchun Chen, Xiaochuan Chen, Matthieu Willot, and
Jieping Zhu*
Dedicated to Professor Yulin Li
on the occasion of his retirement
The ecteinascidins, a family of tetrahydroisoquinoline alkaloids isolated from the Caribbean tunicate Ecteinascidia
turbinata,[1] display a wide range of antitumor and antimicrobial activities.[2] One member of this family, ecteinascidin 743
(Et 743, 1; Scheme 1), is currently in late phase II/III clinical
trials against ovarian, endometrium, and breast cancer, and
several other types of sarcoma. The restricted natural
availability of the ecteinascidins (1 g of Et 743 from 1 ton of
tunicate) in conjunction with their potent antiproliferative
activities and complex molecular architecture has made them
attractive synthetic targets.[3] Since the landmark synthesis of
Et 743 by Corey and co-workers in 1996,[4] Fukuyama and coworkers[5] and our research group[6] have also completed total
syntheses of this molecule, and Danishefsky and co-workers[7]
very recently reported a formal total synthesis of Et 743. A
semisynthesis of Et 743 from cyanosafracin B was developed
by Cuevas, Manzanares, and co-workers at PharmaMar,[8] and
further synthetic approaches have been reported by a number
of research groups.[9?14]
Scheme 1. Structure of representative ecteinascidins.
[*] Dr. J. Chen, X. Chen, M. Willot, Dr. J. Zhu
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-Yvette Cedex (France)
Fax: (+ 33) 1-69077247
[**] Financial support from the CNRS and the Institut de Chimie des
Substances Naturelles are gratefully acknowledged.
Supporting information for this article (experimental procedures,
product characterization, and copies of 1H and 13C NMR spectra of
synthetic Et 597 (3) and Et 583 (4)) is available on the WWW under or from the author.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2006, 118, 8196 ?8200
Ecteinascidins 597 (Et 597, 3) and 583 (Et 583, 4;
Scheme 1) are putative biosynthetic precursors of other
ecteinascidins.[1d, 15] Although the cytotoxicity of Et 597 (3),
which lacks the third tetrahydroisoquinoline unit, is generally
2.5?10 times less potent than that of Et 743 against P 388,
A 549, HT 29, and CV-1 cell lines, its antiproliferative activity
is even greater than that of taxol and camptothecin.[1d] In
continuation of our research towards the development of an
efficient synthetic route to this family of marine natural
products and on the structure?activity relationships (SARs)
of these compounds, we became interested in the synthesis of
Et 597 (3) and Et 583 (4). In a different approach to our
previous strategy,[6] we envisaged that we could take advantage of the presence of two free hydroxy groups in ring A of 3
and 4, as illustrated in Scheme 2. We planned to construct the
Scheme 2. Retrosynthetic analysis of Et 597 (3) and Et 583 (4).
Alloc = allyloxycarbonyl, Boc = tert-butoxycarbonyl.
highly oxygenated A?B ring system by starting from phenol 7
and tetrahydroisoqinoline 8 and carrying out a sequence of
phenolic aldol condensations followed by a Pictet?Spengler
reaction. An intramolecular Strecker reaction would then
afford the entire A?B?C?D?E pentacycle, whereupon the
closure of the 10-membered lactone by formation of the
carbon?sulfur bond would lead to the natural products.
The synthesis of the aromatic segment 7 is summarized in
Scheme 3. 3-Methoxy-4-hydroxybenzaldehyde (9) was converted into 10 through a well-established three-step sequence.
Interestingly, ortho lithiation of 10 followed by the addition of
methyl iodide[16] gave a compound in which both the aromatic
ring and the TBS protecting group had been methylated.
Under optimized conditions (3 equivalents of nBuLi, 4 equivalents of MeI), the dual-methylation product 11 was isolated
in 92 % yield. The MOM group could be removed without
touching the silyl ether by treatment with TMSBr to provide
phenol 7 in excellent yield.[17]
Our synthetic route to the pentacyclic compound 18 is
depicted in Scheme 4. The synthesis of the tetrahydroisoquinoline 12 featured a highly diastereoselective Pictet?
Spengler condensation of the (S)-Garner aldehyde with (S)-3hydroxy-4-methoxy-5-methylphenylalanol.[6, 18] The selective
Angew. Chem. 2006, 118, 8196 ?8200
Scheme 3. Synthesis of the A-ring unit 7: a) TBSCl, imidazole, DMF,
RT, 98 %; b) mCPBA, CHCl3, 45 8C; then Na2CO3, MeOH, RT, 85 %;
c) MOMCl, DIPEA, CH2Cl2, 0 8C!reflux, 96 %; d) nBuLi, THF, 10 8C;
then MeI, 78 8C!RT, 92 %; e) TMSBr, CH2Cl2, 20!0 8C, 90 %.
TBS = tert-butyldimethylsilyl, mCPBA = m-chloroperbenzoic acid,
MOM = methoxymethyl, DIPEA = N,N-diisopropylethylamine,
DMF = N,N-dimethylformamide.
hydrolysis of the oxazolidine moiety in 12 was more difficult
than expected. Eventually, reaction conditions that were
previously developed for the cleavage of acetonides
(CeCl3�2O, oxalic acid, acetonitrile, room temperature)
afforded alcohol 13 in 91 % yield.[19] Swern oxidation[20] of the
primary alcohol furnished the corresponding aminoaldehyde
8, which without purification underwent the stereoselective
phenolic aldol condensation with the magnesium phenolate of
7[21, 22] to provide the syn aminoalcohol 14 in 74 % yield. The
anti aminoalcohol was neither isolated nor detected. The
existence of rotamers made NMR spectroscopic analysis of 14
difficult, and it was hard to determine if this product was a
mixture of two diastereomers with respect to the stereogenic
silicon center.[23] Nevertheless, the question of diastereomers
was of no consequence, as the silyl protecting group was due
to be removed in the next step. Compound 14 was transformed into aminoalcohol 15 in excellent overall yield by a
three-step sequence: 1) protection of the phenol and secondary alcohol as the corresponding methoxymethyl ethers,
2) simultaneous removal of the N-Boc and O-silyl protecting
groups according to the procedure of Sakaitani and
Ohfune,[24] and 3) hydrolysis of the acetate. The Pictet?
Spengler reaction[25] of 15 and TrocOCH2CHO (16; prepared
in two steps from ethyleneglycol)[26] was the key step of our
synthesis. To our pleasure, the desired transformation proceeded efficiently in dichloromethane in the presence of
acetic acid and 3-F molecular sieves to provide 17 as a single
diastereomer in 90 % yield. Swern oxidation of the aminoalcohol 17 followed by a zinc chloride catalyzed intramolecular Strecker reaction provided aminonitrile 18 as a single
stereoisomer to complete the highly efficient construction of
the pentacyclic ring system.
The relative configuration of compound 17 was determined upon its conversion into 19. The characteristic NOEs
observed between H1/H3, H3/H4, and H11/H13 (ecteinascidin numbering) indicated that the configuration of 19, and
hence that of 17, is 1R, 3R, 4R, 11R, 13S. The configuration at
C21 was determined to be R by detailed NMR spectroscopic
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 4. Synthesis of the pentacyclic compound 18: a) CeCl3�H2O, oxalic acid, acetonitrile, RT, 91 %; b) oxalyl chloride, DMSO, CH2Cl2, 60 8C,
then Et3N; c) MeMgCl, THF, 7; then 8, CH2Cl2, RT, 74 %; d) MOMCl, DIPEA, CHCl3, 0 8C!reflux, 88 %; e) TBSOTf, 2,6-lutidine, CH2Cl2, 78 8C!
RT; then KF, MeOH, RT, 86 %; f) K2CO3, MeOH, RT, 94 %; g) AcOH, TrocOCH2CHO (16), 3-H MS, CH2Cl2, RT, 90 %; h) oxalyl chloride, DMSO,
CH2Cl2, 60 8C; then TMSCN, ZnCl2, CH2Cl2, RT, 87 %. DMSO = dimethyl sulfoxide, Tf = trifluoromethanesulfonyl, TMS = trimethylsilyl,
Troc = 2,2,2-trichloroethoxycarbonyl.
studies of the N-de-Alloc derivative 20 (NOEs observed for
H21/H22 and H14/H21; Scheme 5).
The high diastereoselectivity observed in the condensation of 15 and 16 could be explained by assuming that the
iminium intermediate had a trans configuration and that the
substituents at C3 and C4 were both pseudoequatorial (A,
Scheme 5).[27] However, at the present stage an alternative
sequence involving a phenolic aldol condensation and b elimination to give the orthoquinone methide intermediate B
(Scheme 5) followed by intramolecular Michael addition of
the tethered amine can not be eliminated as a possibility.[28] It
is nevertheless interesting to note that the presence of the free
Scheme 5. Structures for the discussion of configuration and possible
reaction pathways.
phenol group in ring A is essential to the success of the
reaction; the condensation of amine 21 with 2-benzyloxyacetaldehyde (or ethyl glyoxylate) failed to provide the
desired tetrahydroisoquinoline.
The total synthesis of Et 597 (3) and Et 583 (4) was
completed as shown in Scheme 6. Unmasking of the Trocprotected primary alcohol under reductive conditions followed by chemoselective allylation of the phenol group
provided compound 22, which was coupled with (R)-N-TrocS-4,4?,4??-trimethoxytritylcysteine to afford the corresponding
ester 23 in excellent yield. The cyclization of 23 was examined
under a variety of reaction conditions; the acid (p-toluenesulfonic acid, TFA, MeSO3H, TMSBr), the solvent (CH2Cl2,
toluene, 2,2,2-trifluoroethanol, MeCN), and the temperature
were varied, and the reaction was carried out in the presence
or absence of molecular sieves. Unfortunately, no combination provided the desired 10-membered lactone 25. The
attempted cyclization of phenol 28 also met with failure. We
then decided to separate the S-deprotection and cyclization
steps. Removal of the S-4,4?,4??-trimethoxytrityl group from 23
with Et3SiH/TFA afforded the stable thiol 24 in 88 % yield
after flash column chromatography.[29] Gratifyingly, the treatment of thiol 24 with TMSBr afforded the bridged macrocycle
25, after the phenol had been masked as the corresponding
acetate, in 60 % yield.[30] In this simple experiment, a complex
reaction sequence involving O-MOM deprotection, 1,4elimination to give the orthoquinone methide,[31] and macrocyclization through an intramolecular Michael addition
occurred in a highly ordered manner to bring about the key
CS bond formation.
Simultaneous removal of the N-Alloc and O-allyl functionalities as described by GuibG and co-workers[32] provided
amine 26 in 85 % yield. A sequence of reductive N methylation, removal of the N-Troc group (zinc/AcOH), and conversion of the aminonitrile functionality into a hemiaminal
(AgNO3 in a mixture of acetonitrile and water) afforded
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2006, 118, 8196 ?8200
Scheme 6. Synthesis of Et 597 (3) and Et 583 (4): a) Zn, AcOH, Et2O, RT, 90 %; b) allyl bromide, K2CO3, acetonitrile, RT, 94 %; c) EDCI, DMAP, (R)N-Troc-S-4,4?,4??-trimethoxytritylcysteine, CH2Cl2, RT, 93 %; d) Et3SiH, TFA, CH2Cl2, RT, 87 %; e) TMSBr, CH2Cl2, 20 8C!10 8C; f) Ac2O, pyridine,
DMAP, CH2Cl2, RT, 60 %; g) [Pd(PPh3)4], nBu3SnH, AcOH, CH2Cl2, RT, 85 %; h) CH2O, NaBH3CN, AcOH, MeCN/MeOH, RT, 95 %; i) Zn, AcOH,
Et2O, RT, 89 % for Et 597, 86 % for Et 583; j) AgNO3, MeCN/H2O, RT, 92 % for 3, 88 % for 4. DMAP = 4-dimethylaminopyridine, TFA = trifluoroacetic acid, EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
ecteinascidin 597 (3) in excellent overall yield. Similarly,
amine 26 was converted into ecteinascidin 583 (4) in a twostep sequence. Synthetic Et 597 (3) and Et 583 (4) exhibited
physical, spectroscopic, and spectrometric characteristics (1H,
C NMR, IR, [a]D, and HRMS) identical to those reported
for the natural products.
In summary, convergent total syntheses of Et 597 (3) and
Et 583 (4) have been completed for the first time from readily
accessible starting materials. Notable features of our
approach include: 1) a stereoselective aldol reaction for the
coupling of the A-ring moiety 7 with the D?E unit 8, 2) a
highly stereoselective Pictet?Spengler reaction for the construction of the B ring, and 3) TMSBr-promoted macrocyclization of the thiol 24 to give the 1,4-bridged 10-membered
ring. This straightforward synthesis does not require sophisticated reaction conditions and should potentially be amenable to large-scale production. We are currently exploiting
this strategy for the synthesis of ecteinascidin analogues for
detailed SAR studies.[33]
Received: August 4, 2006
Published online: November 13, 2006
Angew. Chem. 2006, 118, 8196 ?8200
Keywords: alkaloids � antitumor agents � asymmetric synthesis �
marine natural products � Pictet?Spengler reaction
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